DOI: 10.1378/chest.121.6.1988 2002;121;1988-1999 Chest Ayman O. Soubani and Pranatharthi H. Chandrasekar * The Clinical Spectrum of Pulmonary Aspergillosis This information is current as of April 12, 2006 http://www.chestjournal.org/cgi/content/full/121/6/1988 located on the World Wide Web at: The online version of this article, along with updated information and services, is 0012-3692. reproduced or distributed without the prior written permission of the copyright holder. ISSN: Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF may be Dundee monthly since 1935. Copyright 2005 by the American College of Chest Physicians, 3300 CHEST is the official journal of the American College of Chest Physicians. It has been published at Massachusetts General Hospital on April 12, 2006 www.chestjournal.org Downloaded from
Ayman O. Soubani and Pranatharthi H. Chandrasekar *The Clinical Spectrum of Pulmonary Aspergillosis
This information is current as of April 12, 2006
http://www.chestjournal.org/cgi/content/full/121/6/1988located on the World Wide Web at:
The online version of this article, along with updated information and services, is
0012-3692. reproduced or distributed without the prior written permission of the copyright holder. ISSN:Road, Northbrook IL 60062. All rights reserved. No part of this article or PDF may be
Dundeemonthly since 1935. Copyright 2005 by the American College of Chest Physicians, 3300 CHEST is the official journal of the American College of Chest Physicians. It has been published
at Massachusetts General Hospital on April 12, 2006 www.chestjournal.orgDownloaded from
Ayman O. Soubani, MD; and Pranatharthi H. Chandrasekar, MD
Aspergillus is a ubiquitous fungus that causes a variety of clinical syndromes in the lung, rangingfrom aspergilloma in patients with lung cavities, to chronic necrotizing aspergillosis in those whoare mildly immunocompromised or have chronic lung disease. Invasive pulmonary aspergillosis(IPA) is a severe and commonly fatal disease that is seen in immunocompromised patients, whileallergic bronchopulmonary aspergillosis is a hypersensitivity reaction to Aspergillus antigens thatmainly affects patients with asthma. In light of the increasing risk factors leading to IPA, such asorgan transplantation and immunosuppressive therapy, and recent advances in the diagnosis andtreatment of Aspergillus-related lung diseases, it is essential for clinicians to be familiar with theclinical presentation, diagnostic methods, and approach to management of the spectrum ofpulmonary aspergillosis. (CHEST 2002; 121:1988–1999)
Abbreviations: ABPA � allergic bronchopulmonary aspergillosis; BMT � bone marrow transplantation;CNA � chronic necrotizing aspergillosis; IPA � invasive pulmonary aspergillosis
A spergillus is a ubiquitous soil-dwelling organismfound in organic debris, dust, compost, foods,
spices, and rotted plants. There are approximately200 species of Aspergillus; however, only a few areknown to be pathogenic for humans. Aspergillusfumigatus, Aspergillus flavus, and Aspergillus nigerare the most commonly encountered species, butother species, like Aspergillus terreus, Aspergillusclavatus, Aspergillus niveus, and Aspergillus nidu-lans, have rarely been reported to cause disease inhumans.1
Aspergillus, like other filamentous fungi, is pri-marily acquired from an inanimate reservoir, usu-ally by the inhalation of airborne spores. Theorganism grows best at 37°C, and the small spores(2 to 3 �m) are easily inhaled and deposited deepin the lungs, leading to a variety of clinical syn-dromes (Fig 1). Although these are distinct pul-monary entities, on rare occasions one conditionmay change to another; for example, an aspergil-loma may change to invasive pulmonary asper-gillosis (IPA).2,3
This article reviews the clinical spectrum of pul-monary aspergillosis, emphasizing the risk factors,clinical picture, and recent advances in diagnosticand therapeutic approaches.
Aspergilloma
This is the most common and best-recognizedform of pulmonary involvement due to Aspergillus.The aspergilloma (fungal ball) consists of masses offungal mycelia, inflammatory cells, fibrin, mucus,and tissue debris, usually developing in a preformedlung cavity. Although other fungi may cause theformation of a fungal ball (for example, Zygomycetesand Fusarium), Aspergillus spp (specifically, A fu-migatus) are by far the most common etiologicagents.
The true incidence of aspergilloma is not known.In a study4 of 544 patients with pulmonary cavitiessecondary to tuberculosis, 11% had radiologicevidence of aspergilloma. The most common pre-disposing factor is the presence of a preexistinglung cavity formed secondary to tuberculosis, sarcoid-osis, bronchiectasis, bronchial cysts and bullae, ankylos-ing spondylitis, neoplasm, or pulmonary infarction.5,6
Of these, tuberculosis is the most frequently associatedcondition.7 Occasionally, aspergilloma has been de-scribed in cavities caused by other fungal infections.8,9
It is believed that inadequate drainage facilitates thegrowth of Aspergillus on the walls of these cavities.
*From the Divisions of Pulmonary, Critical Care, and Sleep Medi-cine (Dr. Soubani) and Infectious Diseases (Dr. Chandrasekar),Wayne State University School of Medicine, Detroit, MI.Manuscript received February 27, 2001; revision acceptedAugust 29, 2001.Correspondence to: Ayman O. Soubani, MD, Harper UniversityHospital, Division of Pulmonary, Critical Care, and Sleep Med-icine, 3990 John R-3 Hudson, Detroit, MI 48201; e-mail:[email protected]
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Usually, the fungus does not invade the surroundinglung parenchyma or blood vessels; exceptions, how-ever, have been noted.2,10
The natural history of aspergilloma is variable. Inthe majority of cases, the lesion remains stable,however, in approximately 10% of cases, it maydecrease in size or resolve spontaneously withouttreatment.11 Rarely, the aspergilloma increases insize.12
Clinical Picture
An aspergilloma may exist for years without caus-ing symptoms. Most patients will experience mildhemoptysis, but severe hemoptysis may occur, par-ticularly in patients with underlying tuberculosis.13
Bleeding usually occurs from bronchial blood ves-sels. Theories on the cause of the hemoptysis includelocal invasion of blood vessels lining the cavity,endotoxins released by the fungus with hemolyticproperties, and mechanical friction of the aspergil-loma with the cavity wall blood vessels.2,14,15 Themortality rate from hemoptysis ranges between 2%and 14%.16–20 Other symptoms include chroniccough and dyspnea that are probably more related tothe underlying lung disease. Fever is rare unlessthere is secondary bacterial infection.
Risk factors associated with poor prognosis ofaspergilloma are severe underlying disease, increas-ing size or number of lesions as seen on chestradiographs, immunosuppression (including cortico-steroid treatment), increasing Aspergillus-specificIgG titers, recurrent large-volume hemoptysis, andunderlying sarcoidosis or HIV infection.21
Diagnosis
Aspergilloma usually comes to clinical attention asan incidental finding on a routine chest radiograph orduring an evaluation of hemoptysis. Radiologically,aspergilloma is evident as an upper-lobe, mobile,intracavitary mass with an air crescent in the periph-ery.22 The adjacent pleura may be thickened. Attimes, the mass may be difficult to see on a routinechest radiograph, and tomography or chest CT scanmay be necessary to visualize the aspergilloma 23 (Fig2). A change in the position of the aspergilloma witha change of position of the patient is an interestingbut variable sign.23 The differential diagnosis of thisradiologic appearance includes hematoma, neo-
Figure 1. The clinical spectrum of conditions resulting from the inhalation of Aspergillus spores.ICH � immunocompromised host.
Figure 2. Chest CT scan of a patient with a history of lungcancer and tuberculosis, who developed aspergilloma after un-dergoing resection of the right upper lobe.
plasm, abscess, hydatid cyst, and Wegener granulo-matosis. It is important to note that aspergilloma maycoexist with any of the above conditions.24,25
A sputum examination may reveal the presence ofAspergillus but is negative in 50% of the cases.26
Serum IgG antibodies to Aspergillus are positive inalmost all cases; however, they may be falsely nega-tive in the rare cases of aspergilloma due to speciesother than A fumigatus or in patients receivingcorticosteroid therapy.10 Immediate skin reactivity ismuch less helpful in the evaluation of aspergillomaand is positive only in a minority of patients.26
Treatment
In asymptomatic patients, no therapy is warranted.There is no consistent evidence that aspergillomaresponds to antifungal agents, and these drugs rarelyachieve the minimal inhibitory concentrations withinthe lung cavities.27 Inhaled, intracavitary, and endo-bronchial instillations of antifungal agents have beentried with no consistent success.19,28,29 In addition,systemic antifungal therapy using IV amphotericin Bfailed to show a benefit in patients with aspergil-loma.30 Itraconazole therapy has been tried withvariable results.31–33 Bronchial artery embolizationrarely results in control of hemoptysis because of themassive collateral blood vessels; however, this pro-cedure should be considered as a temporizing mea-sure in patients with life-threatening hemoptysis.34
The surgical treatment of aspergilloma is associatedwith relatively high mortality rate that ranges be-tween 7% and 23%.15–17,35–38 The most commoncauses of death following surgery are severe under-lying lung disease, pneumonia, acute myocardialinfarction, and IPA.19,38 In addition, there is signifi-cant postoperative morbidity, including bleeding,residual pleural space, bronchopulmonary fistula,empyema, and respiratory failure. A recent report39
of 87 patients who were operated on for pulmonaryaspergilloma revealed a postoperative mortality rateof 5.7%. Another report38 showed a lower mortalityrate of 1.5% and morbidity of 18% in the surgicaltreatment of aspergilloma; however, most of thepatients were young with adequate respiratory re-serve, and tuberculosis was the underlying lungdisease in the vast majority of the patients.
In summary, observation alone is adequate in mostcases of aspergilloma. Medical therapy with bed rest,humidified oxygen, cough suppressants, and posturaldrainage is helpful in cases of mild hemoptysis. Thesurgical approach needs to be considered in patientswith massive hemoptysis and adequate pulmonaryreserves.20 The role of itraconazole is yet to bedetermined.
Chronic Necrotizing Aspergillosis
Also called semi-invasive aspergillosis, this entitywas first described in two reports in 1981 and1982.40,41 Chronic necrotizing aspergillosis (CNA) isan indolent, destructive process of the lung due toinvasion by Aspergillus species (usually A fumigatus).This entity is different from aspergilloma in thatthere is local invasion of the lung tissue, and apreexisting cavity is not needed, although a cavitywith a fungal ball may develop in the lung as asecondary phenomenon due to destruction by thefungus. On occasion, an aspergilloma may invade thecavity wall, causing local parenchyma destruction, asseen in patients with CNA.42 CNA is also differentfrom invasive aspergillosis. The former, in contrast tothe latter, is a chronic process that progresses slowlyover months to years, and there is no vascularinvasion or dissemination to other organs.40
CNA is usually seen in middle-aged and elderlypatients with documented or suspected underlyinglung diseases like COPD, inactive tuberculosis, pre-vious lung resection, radiation therapy, pneumoco-niosis, cystic fibrosis, lung infarction, or, rarely,sarcoidosis.43 It also has been described in patientswith mild immunosuppression, including those withdiabetes mellitus, those with poor nutrition, thoseundergoing low-dose corticosteroid therapy, andthose with connective tissue diseases such as rheu-matoid arthritis and ankylosing spondylitis.40
The patient usually presents with fever, cough,sputum production, and weight loss of 1 to 6 months’duration. A minority of the patients may be asymp-tomatic.40 The chest radiograph usually shows aninfiltrative process in the upper lobes or the superiorsegments of the lower lobes. A fungal ball may beseen in nearly one half of the cases.40 Adjacentpleural thickening is a characteristic finding and maybe an early indication of a locally invasive process.41
The diagnosis is confirmed by a histologic demon-stration of tissue invasion by the fungus and thegrowth of Aspergillus species on a culture. However,the yield of transbronchial biopsy specimens orpercutaneous aspirates is relatively poor, and a tho-racoscopic or open-lung biopsy is rarely performedin these patients. So, a clinical diagnosis of CNAcould be made using the following criteria:
• Clinical and radiologic features consistent with thediagnosis;
• Isolation of Aspergillus species by culture fromsputum or from bronchoscopic or percutaneoussamples; and
• Exclusion of other conditions with similar presen-tations, such as active tuberculosis, atypical myco-bacterial infection, chronic cavitary histoplasmosis,or coccidioidomycosis.
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Other helpful but nondiagnostic tests includeserum IgG antibodies to Aspergillus (positive resultsin � 90% of the patients) and immediate skin reac-tivity for Aspergillus antigens.
Treatment with antifungal medications is indi-cated once the diagnosis is made. The response totherapy with IV amphotericin B is generally favor-able.40,42 However, therapy with itraconazole hasemerged as an effective alternative to the relativelytoxic amphotericin B.42,44 Surgical resection is gen-erally reserved for healthy young patients with focaldisease and good pulmonary reserves, patients nottolerating antifungal therapy, and patients with re-sidual localized but active disease despite adequateantifungal treatment. In the initial series by Binderet al,40 90% of patients who underwent surgicalresections had good responses. However, there weresignificant postoperative complications, and one pa-tient died.40
The long-term prognosis for patients with CNA isnot well-documented. In the original series,40 73% ofthe patients were alive 1 to 2 years following therapy,and the majority of deaths was due to other causes.
IPA
The incidence of IPA has been on the rise since itwas first described in 1953.45 Groll et al46 docu-mented a rise in the rate of invasive mycoses from0.4 to 3.1% of all autopsies performed between 1978and 1992. In addition, invasive aspergillosis in-creased from 17% of all mycoses found on autopsy atthe beginning of the study to 60% at the end of the14-year study period.
The vast majority of IPA cases are seen in immu-nocompromised patients. The risk factors are sum-marized in Table 1.47–51 Neutropenia is the mostimportant risk factor, and it is estimated that IPAaccounts for 7.5% of all infections in neutropenicpatients following induction therapy for acute my-elogenous leukemia.47 The risk of IPA increases withthe duration of neutropenia (ie, neutrophil count,� 500 cells/�L) and is estimated to be 1% per dayfor the first 3 weeks, after which time it increases to4% per day.47 Transplantation, especially lung and
bone marrow transplantation (BMT), is another in-creasingly significant risk factor for IPA.52 It isestimated that 5% of BMT recipients develop IPAwith mortality rates ranging between 30% and80%.53–55 In BMT recipients, IPA may be seen in thefirst few weeks after the procedure with delayedengraftment or graft failure, and more commonly inthe setting of treatment with corticosteroids forgraft-vs-host disease. The increased risk of IPA inpatients undergoing transplantation is related tomultiple immune defects including prolonged neu-tropenia in the pre-engraftment phase of BMT, andthe use of multiple antirejection or anti-graft-vs-hostdisease therapy, including corticosteroids and cyclo-sporine. In addition, other factors that predisposepatients to fungal infections in general, such asparenteral nutrition, use of multiple antibiotics, andprolonged hospitalization, increase the risk of IPAfollowing transplantation. IPA also has been re-ported increasingly in patients with HIV infection.51
While most HIV-infected patients have the same riskfactors for Aspergillus infection as those in otherpatient populations (such as patients with neutrope-nia and those receiving corticosteroid therapy), thereare a growing number of reports of IPA in AIDSpatients without the traditional risk factors.56,57 Be-sides the usual clinical picture of IPA, there isincreased incidence of tracheobronchial involve-ment.58 The response to therapy is particularly poorin the HIV-infected population.51
Rarely, IPA has been reported59,60 in apparentlyimmunocompetent patients or in those individualswho are mildly immunocompromised, such as pa-tients with alcoholism, chronic liver disease, or dia-betic ketoacidosis. In addition, IPA is increasinglyrecognized in patients with advanced COPD, espe-cially those treated with oral corticosteroids.61,62 In arecent review63 of 545 patients with invasive as-pergillosis, BMT was the most frequent risk factor(32%; autologous BMT, 7%; allogeneic BMT, 25%),followed by hematologic malignancy (29%), solidorgan transplantation (9%), and AIDS (8%). In 2% ofpatients, no underlying risk factors were identified.
Clinical Picture
The lower respiratory tract is almost always theprimary focus of infection as a result of the inhalationof the infectious spores. Less commonly, IPA maystart in locations other than the lungs, like thesinuses, the GI tract, or the skin (ie, resulting fromthe insertion of IV catheters, prolonged skin contactwith adhesive tapes, or burns).64–67
Consequently, patients usually present with respi-ratory symptoms that are consistent with broncho-pneumonia, with fever, cough, sputum production,
2. Corticosteroid therapy (especially prolonged, high-dose therapy)3. Transplantation (highest risk is with lung and bone marrow)4. Hematologic malignancy (risk is higher with leukemia)5. Cytotoxic therapy6. AIDS (risk increases with lower CD4 count)
and dyspnea. Two other symptoms that are signifi-cant and that raise the possibility of IPA in theappropriate clinical setting are pleuritic chest pain(due to small pulmonary infarctions secondary tovascular invasion) and hemoptysis that is usually mildbut could be massive. IPA is one of the mostcommon causes of hemoptysis in neutropenic pa-tients; and has been reported to be associated withcavitation that occurs with neutrophil recovery.68
Other pulmonary manifestations include isolatedtracheobronchitis with severe inflammation of theairways that is associated with ulcerations and plaqueformation. This may lead to airway obstruction andsecondary atelectasis. This form of IPA has beenmost commonly reported in patients with AIDS andin lung transplant recipients 69,70
With the predilection of Aspergillus to invadeblood vessels, IPA commonly leads to areas ofinfarction and hemorrhage in the primary organ(usually the lungs), and the organism spreads hema-togenously to other organs, most commonly thebrain (leading to seizures, ring-enhancing lesions,cerebral infarctions, intracranial hemorrhage, men-ingitis, and epidural abscess), and less commonlyskin, kidneys, pleura, heart, esophagus, liver, or anyother site.71
Diagnosis
The diagnosis of IPA is difficult. A high index ofsuspicion is necessary in patients with risk factors forinvasive aspergillosis. The diagnosis is best made bydemonstrating the presence of septate, acute,branching hyphae in the lung tissue sample alongwith a culture that is positive for Aspergillus from thesame site. Methenamine-silver and periodic acid-Schiff stains are the usual stains to demonstrate thecharacteristic hyphae. Other fungi such as Fusariumand Scedosporium may have similar appearances,thus increasing the importance of performing aculture for the accurate identification of the fungus.
The presence of the Aspergillus species in sputumsamples could be due to colonization of the airway;however, in the immunocompromised patient spu-tum culture positivity may be the only indication ofIPA. Studies72–74 have shown that sputum samplesthat are positive for Aspergillus in patients withleukemia or in those who have undergone BMT havea positive predictive value of 80 to 90%. On the otherhand, a sputum sample that is negative for Aspergil-lus does not exclude the diagnosis of IPA, sincenegative sputum studies have been noted in 70% ofpatients with confirmed IPA.75 Blood cultures rarelyhave positive results.76
The chest radiograph often shows nonspecificchanges. The lesions that are suggestive of IPA
include rounded densities, pleural-based infiltratesthat are suggestive of pulmonary infarctions, andcavitation. Pleural effusions are uncommon.77,78 Thechest CT scan, especially with high-resolution im-ages, is a much more helpful tool in the diagnosis ofIPA. It leads to earlier diagnosis, and aids furtherdiagnostic studies like bronchoscopy and open-lungbiopsy.79,80 The routine use of high-resolution chestCT scans in patients with suspected IPA has beenassociated with better outcomes, probably due toearlier diagnosis. Of the 156 patients who underwentchest CT scans in the report by Patterson et al,63
85% had findings that were suggestive of IPA.Typical chest CT scan findings are multiple nodules(Fig 3), the halo sign, which is an early radiologicsign that appears as a zone of low attenuation due tohemorrhage surrounding the pulmonary nodule,81
and the air crescent sign, which is a crescent-shapedlucency in the region of the original nodule second-ary to necrosis.82 The air crescent sign usually cor-relates with recovery from neutropenia and is arelatively late sign.83 The last two radiologic signs arerelatively specific for IPA, but they are neithersensitive nor pathognomonic; other infections likenocardiosis and zygomycoses may have a similarappearance.81,82
BAL is helpful in the diagnosis of IPA, especiallyin patients with diffuse lung involvement. The BALfluid is tested by fungal smear and culture. Thespecificity of a positive result of BAL fluid testing isvery high, reaching 97%,84 but the sensitivity isreported to be approximately 30 to 50%.84,85 Trans-bronchial biopsies have not been shown to add muchto the results of BAL and are associated with in-creased risks.19 Open or thoracoscopic lung biopsiesare generally the “gold standard” in the diagnosis of
Figure 3. Chest CT scan of a patient with chronic lymphocyticleukemia and histologically proven IPA showing multiple pulmo-nary nodules.
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pulmonary problems in immunocompromised pa-tients; however, in the case of IPA, this procedure isknown to be associated with false-negative results. Ina study86 of 15 patients who had undergone open-lung biopsies, the presence of IPA was missed in 3.Thus, open-lung biopsy is reserved for patients inwhom the diagnosis of IPA remains uncertain de-spite results from the mentioned studies, and whensuch a procedure is expected to have an impact onthe patients’ management and outcome.
Serology has not been useful in the diagnosis ofIPA. Aspergillus antibody detection is not useful,probably due to the poor immune response ofpatients with IPA and the rapidity with which theinfection occurs, not giving enough time for anadequate antibody response.87
There has been increasing interest in Aspergillusantigen detection from serum and BAL samples.Some studies88 suggest that antigenemia may bedetected before the presence of clinical features ofIPA. A sandwich enzyme-linked immunosorbent as-say technique that utilizes monoclonal antibodies togalactomannan (ie, the cell wall glycoprotein thatbinds lectin) has been developed to detect theAspergillus antigen in serum, urine, and BAL fluidand has a reported sensitivity and specificity of� 90%.88–92 This method, while commercially avail-able in Western Europe, has not yet been approvedin the United States.
Polymerase chain reaction is another experimentalmethod with which to diagnose IPA by the detectionof Aspergillus DNA in BAL fluid and serum. Theextrasensitive nature of this method and the ubiqui-tous presence of the fungus create a high likelihoodof false-positive results.93,94
The National Institute of Immunology, Allergy,and Infectious Diseases has provided a workingcase definition. The diagnosis of IPA is definitewhen tissue histopathology shows the hyphae, withor without a positive culture for Aspergillus fromthe same site, or a positive culture from tissueobtained by an invasive procedure such as trans-bronchial biopsy, percutaneous needle aspiration,or open-lung biopsy. The diagnosis of IPA isprobable when the clinical picture is consistentwith the diagnosis, and when two sputum cul-tures or one BAL fluid culture, a bronchial wash-ing culture, or a brushing culture for Aspergillusspecies, or a cytologic examination of the BALfluid shows the characteristic hyphae or positiveAspergillus antigen in the serum or BAL fluid. Thediagnosis is possible when the clinical picture iscompatible without documentation of any myco-logic evidence of IPA.63,95
Treatment
The treatment of IPA is difficult, and the mortalityrate remains high despite recent advances in ther-apy. Empiric therapy should be started as soon asthere is clinical suspicion of IPA, and while a workupis underway. The outcome of therapy is dependenton an early diagnosis, the absence of dissemination,the instigation of intensive antifungal therapy, andthe recovery of the underlying host defense defect,such as the resolution of neutropenia or the taperingof immunosuppression therapy.96–98 In the review byPatterson et al,63 patients who had severe immuno-suppression, such as those who had undergone BMTand had hematologic malignancy, had poor re-sponses to therapy compared to less severely immu-nosuppressed patients (28% vs 51%, respectively).Also, when IPA was limited to the lung, the responsewas better than in patients with disseminated infec-tion (40% vs 18%, respectively). The most widelyused drug in the treatment of IPA is amphotericin B.Its usual dose is 0.6 to 1.2 mg/kg/d; however, higherdoses (ie, 1 to 1.5 mg/kg/d) may be necessary inseverely immunocompromised patients with over-whelming infections.99 The optimal duration of an-tifungal drug therapy is not known, but treatment isrecommended to continue past the period of immu-nosuppression and until the disease appears to beclinically resolved.19 Even with optimal therapy, theresponse rate varies widely between 20% and83%.100
Amphotericin B is known to cause serious sideeffects such as nephrotoxicity, electrolyte distur-bances, and hypersensitivity reactions. Newer lipid-based preparations of amphotericin B (eg, liposomalamphotericin B and lipid complex amphotericin B)have been introduced in an effort to minimize theseside effects. These preparations enable the adminis-tration of higher doses of amphotericin B with lesstoxicity and are indicated in patients who are at highrisk for nephrotoxicity, who develop toxicity whilereceiving amphotericin B, or who respond poorly tothat medication.19,101–104
Itraconazole, a triazole, is another agent that isused in the treatment of IPA, in doses of 200 to 400mg/d.30,105 The drug is available in oral (ie, capsuleand suspension) and IV formulations. The itracon-azole capsule should be avoided in the treatment ofIPA in view of its poor bioavailability. In a largenonrandomized study,95 itraconazole was found toresult in complete or partial response in 39% ofpatients with IPA, and in a failure to respond totreatment in 26%. The results were particularly poorin allogeneic BMT recipients and AIDS patients. Itis reasonable to consider therapy with itraconazole asan alterative to that with amphotericin B in patients
with IPA who are less immunocompromised and inthe late stages of therapy after the initial control ofthe infection with amphotericin B therapy. Becauseof drug-drug interactions, itraconazole needs to beused with caution. The use of combination therapy(for example, amphotericin B with 5-fluorocytosine,rifampin, itraconazole, or ketoconazole) has not beenshown to be more effective in the treatment ofpatients with IPA.106 Trials19 are currently underwaytesting several new promising drugs like voricon-azole, posaconazole, and echinocandin derivatives.Caspofungin, an echinocandin derivative was re-cently approved107 for the treatment of IPA inpatients with refractory infection or those intolerantto conventional therapy.
Other modalities of therapy include surgical resec-tion, which should be considered in cases of massivehemoptysis,108 or the resection of residual localizedpulmonary lesions in patients with continuing immu-nosuppression or those who are expected to havefurther immunosuppressive therapy in the future.109
Surgery has been performed safely in selected neu-tropenic patients.109–111 The surgical outcome ispoor in patients with multiple foci of infection, inthose who have undergone allogeneic BMT, andthose requiring mechanical ventilation.
The value of immunomodulatory therapy such asthat using cytokines (ie, granulocyte colony-stimulat-ing factor, granulocyte macrophage-colony-stimulat-ing factor, or interferon-�) as adjuvant therapy is notclear, and large studies on the safety and efficacy ofthese agents are lacking.112
Given the difficulties in the management of IPA,an important approach to this problem is prophylaxisfor those patients who are at increased risk for IPA.Avoiding the hospitalization of patients in areaswhere there is construction and the use of high-efficiency particulate air or laminar air flow havebeen shown to decrease the rate of IPA in somestudies.113 Also chemoprophylaxis using low-doseamphotericin B and intranasal amphotericin B havebeen studied with variable results.114,115 Currentlychemoprophylaxis trials using itraconazole andposaconazole are underway in allogeneic BMT re-cipients.
Allergic Bronchopulmonary Aspergillosis
Allergic bronchopulmonary aspergillosis (ABPA) isa hypersensitivity reaction to Aspergillus antigens,mostly due to A fumigatus. It is typically seen inpatients with long-standing asthma or cystic fibrosis,and it is estimated that 7 to 14% of corticosteroid-dependent asthma patients and 6% of patients withcystic fibrosis meet the diagnostic criteria for
ABPA.116,117 The factors leading to ABPA are notclearly understood. It is believed that Aspergillus-specific, IgE-mediated type I hypersensitivity reac-tions and specific IgG-mediated type III hypersen-sitivity reactions play a central role in thepathogenesis of ABPA.118,119 Other host factors,including cellular immunity, may contribute to thepathologic changes seen in ABPA.120,121 Since thediagnosis of ABPA is usually made on clinicalgrounds, lung biopsies are rarely performed. In astudy122 of 18 pathologic specimens from patientswith ABPA, the most significant findings involvedthe bronchi and bronchioles with bronchocentricgranulomas in 15 specimens and mucoid impactionin 11. Other findings included granulomatous in-flammation with histiocytes and lymphocytes, in-creased numbers of eosinophils, and exudative bron-chiolitis. Fungal hyphae were commonly seenwithout evidence of tissue invasion.122
Diagnosis
ABPA is usually suspected on clinical grounds, andthe diagnosis is confirmed by radiologic and sero-logic testing. The patient usually presents withwheezing, expectoration of brown mucus plugs,pleuritic chest pain, and fever.123 The chest radio-graph findings may be normal in the early stages ofthe disease. During acute exacerbations, the typicalfindings are fleeting pulmonary infiltrates that tendto be in the upper lobe and central in location. Theremay be loss of volume due to mucoid impaction ofthe airways. This latter manifestation may present asband-like opacities emanating from the hilum withrounded distal margins (gloved finger appear-ance).124 At later stages, central bronchiectasis andpulmonary fibrosis develop. The chest CT scan ismore sensitive in demonstrating the above changes.The IgE level serves as a marker for flare-ups andresponses to therapy.125 A positive sputum culturefor A fumigatus is not essential for the diagnosis, andindeed in rare cases a syndrome similar to ABPA istriggered by fungi other than Aspergillus. Immediateskin reactivity to A fumigatus antigens and elevatedlevels of serum IgG antibodies to Aspergillus areusually present.118 Lung biopsy is rarely performedfor the diagnosis of ABPA.
Greenberger and Patterson recently modified thediagnostic criteria for ABPA (Table 2).123,125 Not allof these criteria need to be present to diagnoseABPA. Withholding therapy until the developmentof all clinical symptoms and evidence of bronchiec-tasis may lead to a missed diagnosis in a significantnumber of patients and to delayed treatment result-ing in irreversible pulmonary damage. Therefore,ABPA may be subdivided into the following two
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groups: patients with or without central bronchiec-tasis. The essential criteria for diagnosis of the groupwith ABPA and central bronchiectasis are asthma,immediate skin reactivity to Aspergillus antigens,serum IgE level � 1,000 ng/mL, and central bron-chiectasis. Patients without central bronchiectasisare labeled ABPA-seropositive, and the minimalcriteria for diagnosis are asthma, immediate skinreactivity to Aspergillus, serum IgE level � 1,000ng/mL, history of pulmonary infiltrates, and elevatedlevels of serum IgE and IgG antibodies to A fumiga-tus.127
Patterson et al128 divided this syndrome into fivestages that help to guide the management of thedisease. It is not necessary for a patient to progressthrough all of these stages. Stage 1 (acute stage) ischaracterized by asthma, a markedly elevated IgElevel, peripheral eosinophilia, pulmonary infiltrates,and the presence of IgE and IgG antibodies toA fumigatus. In practice, patients are rarely identi-fied in this stage. In stage II (remission stage), theIgE level falls, but not to the normal range, eosino-philia is absent, and the chest radiograph is clear.Serum IgG antibodies to Aspergillus may be slightlyelevated. Stage III (exacerbation stage) is diagnosedin a patient who is known to have ABPA and issimilar to stage I. The IgE level is usually double thatat baseline. Stage IV (the corticosteroid-dependentstage) occurs when the patient becomes steroid-dependent and attempts to taper the steroid therapy,resulting in an obvious worsening of symptoms andthe development of pulmonary infiltrates. The serumIgE level is usually elevated but may be normal.Frequently, the chest CT scan will show centralbronchiectasis. Unfortunately, the syndrome is diag-nosed in the majority of patients at this stage.129
Stage V (fibrotic stage) is characterized by clinicalfeatures of end-stage lung disease with dyspnea,cyanosis, rales, and cor pulmonale. Clubbing may bepresent. The serum IgE level and eosinophil countmay be low or high. A minority of patients progressto this stage.
Treatment
The mainstay of therapy for ABPA is oral cortico-steroids to suppress the immunologic response to
Aspergillus antigens and the secondary inflammatoryreaction. Treatment with corticosteroids leads to therelief of bronchospasm, the clearing of pulmonaryinfiltrates, and a decrease in IgE level and peripheraleosinophilia.130,131 Oral prednisone is administeredat 0.5 mg/kg/d for 2 weeks then gradually is ta-pered.132 The duration of therapy should be individ-ualized according to the patient’s clinical condition.Most patients, however, require prolonged low-dosecorticosteroid therapy to control their symptoms andminimize relapses.132,133 Inhaled steroids are nothelpful in preventing the progression of lung damageassociated with ABPA.134
Since there are side effects associated with long-term corticosteroid therapy, including an increasedrisk of invasive aspergillosis,135 interest in othermodalities of treatment of ABPA has developed.Recently, a randomized prospective study136 wasperformed to evaluate the role of an antifungalagent, itraconazole, in the management of ABPA.The study showed that 46% of patients treated withitraconazole, 200 mg bid for 16 weeks, had a signif-icant response, which was defined as a 50% reduc-tion in the corticosteroid dose, a decrease of at least25% in the serum IgE concentration, and a 25%improvement in exercise tolerance or pulmonaryfunction test results, or the resolution or absence ofpulmonary infiltrates. There was no significant tox-icity related to this therapy. The study concludedthat patients with ABPA generally benefit fromconcurrent itraconazole therapy and suggested that alower dose of itraconazole (200 mg daily) was equallybeneficial and may be useful as a maintenancetherapy to sustain remission.
Syndromes Related to ABPA
Mucoid Impaction: This feature of ABPA may beseen without asthma or other features of the disease.The patient usually presents with a cough and ex-pectoration of mucus plugs.137 The mucus pluggingmay lead to atelectasis, which may arouse suspicionof endobronchial malignancy.138
Bronchocentric Granulomatosis: This syndrome ischaracterized by necrotizing granulomas that ob-struct and destroy the bronchioles. The Aspergillushyphae are identified within the granulomas in 40 to50% of patients with bronchocentric granulomato-sis.99 The lung parenchyma is marked by the pres-ence eosinophilic inflammatory infiltrates and fibro-sis, however, there is no tissue or vascular invasion bythe Aspergillus. Clinically, the patients are almostalways asthmatic and have a persistent cough withperipheral eosinophilia and increased serum IgElevels. The chest radiograph usually shows solitary or
Table 2—Diagnostic Criteria for ABPA
1. Asthma2. Immediate skin reactivity to Aspergillus3. Serum precipitins to A fumigatus4. Increased serum IgE and IgG to A fumigatus5. Total serum IgE � 1,000 ng/mL6. Current or previous pulmonary infiltrates7. Central bronchiectasis8. Peripheral eosinophilia (1,000 cells/�L)
multiple pulmonary nodules that may be mistakenfor malignancies. The patients usually respond tocorticosteroid therapy.139
Eosinophilic Pneumonitis: Aspergillus rarely hasbeen implicated in the etiology of this syndrome.The patient usually presents with cough, dyspnea,and fever associated with peripheral pulmonary in-filtrates, and an elevation of Aspergillus IgE levels.The diagnosis usually is confirmed by biopsy, andpatients respond well to corticosteroid therapy.140,141
Hypersensitivity Pneumonitis: Also known as ex-trinsic allergic alveolitis, it is a form of hypersensi-tivity granulomatous inflammation of the distal air-ways and lung parenchyma. It is related to intense orrepeated inhalation of various antigens, includingthermophilic bacteria, fungi, bird excreta, and chem-ical agents. This condition has been described inpatients exposed to Aspergillus spores and has beenimplicated in farmer’s lung disease and malt-worker’s lung disease.142 The acute form of thedisease presents within hours of exposure to theantigens with dyspnea, cough, fever, and myalgia.The chest radiograph usually shows interstitial andalveolar nodular infiltrates. Repeated exposures tothe offending antigens lead to a chronic form ofhypersensitivity pneumonitis that is associated withirreversible pulmonary fibrosis.142,143 Serum levels ofIgG antibodies to Aspergillus are elevated when thedisease is due to Aspergillus.144 The managementof the acute form includes avoiding further expo-sure to the offending agents and corticosteroidtherapy.142,145
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Ayman O. Soubani and Pranatharthi H. Chandrasekar *The Clinical Spectrum of Pulmonary Aspergillosis
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